Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.
Circulating tumor cells (CTCs) are shed into the bloodstream by invasive cancers, but the difficulty inherent in identifying these rare cells by microscopy has precluded their routine use in monitoring or screening for cancer. We recently described a high-throughput microfluidic CTC-iChip, which efficiently depletes hematopoietic cells from blood specimens and enriches for CTCs with well-preserved RNA. Application of RNA-based digital PCR to detect CTC-derived signatures may thus enable highly accurate tissue lineage-based cancer detection in blood specimens. As proof of principle, we examined hepatocellular carcinoma (HCC), a cancer that is derived from liver cells bearing a unique gene expression profile. After identifying a digital signature of 10 liver-specific transcripts, we used a cross-validated logistic regression model to identify the presence of HCC-derived CTCs in nine of 16 (56%) untreated patients with HCC versus one of 31 (3%) patients with nonmalignant liver disease at risk for developing HCC (P < 0.0001). Positive CTC scores declined in treated patients: Nine of 32 (28%) patients receiving therapy and only one of 15 (7%) patients who had undergone curative-intent ablation, surgery, or liver transplantation were positive. RNA-based digital CTC scoring was not correlated with the standard HCC serum protein marker alpha fetoprotein (P = 0.57). Modeling the sequential use of these two orthogonal markers for liver cancer screening in patients with high-risk cirrhosis generates positive and negative predictive values of 80% and 86%, respectively. Thus, digital RNA quantitation constitutes a sensitive and specific CTC readout, enabling high-throughput clinical applications, such as noninvasive screening for HCC in populations where viral hepatitis and cirrhosis are prevalent.circulating tumor cells | early cancer detection | hepatocellular carcinoma | blood biopsy | predictive modeling T he shedding by epithelial cancers of circulating tumor cells (CTCs) into the bloodstream underlies the blood-borne dissemination of cancer, although only a small fraction of CTCs gives rise to metastases (1). Enumeration and analysis of CTCs may thus enable noninvasive monitoring of advanced cancers, as well as early detection of invasive but localized tumors before they give rise to viable metastases. Recent advances in CTC isolation provide sensitive and high-throughput platforms to enrich for these rare tumor cells within blood specimens, but antibody staining and microscopic imaging of captured cancer cells remain a critical bottleneck limiting broad application of the technology (2). Classical CTC staining criteria include the presence of cell surface epithelial cell adhesion molecule (EpCAM) and cytoplasmic epithelial cytokeratins and the absence of the hematopoietic CD45 marker (3), but epithelial marker expression is highly variable and extensive imaging criteria must be applied to score immunofluorescent signals reliably from rare cancer cells surrounded by contaminating leukocytes (4). Emerging microfluidic C...
Garlic polysaccharides are great potential agents because of their anti-inflammation, antioxidation, and immunomodulation properties. However, few studies have reported their anti-inflammatory effects on improving the colon system and corresponding intestinal microbiota. Herein, a water-soluble garlic polysaccharide (WSGP) was extracted from Jinxiang garlic to evaluate its effects on ameliorating dextran sulfate sodium (DSS)-induced colitis in a mouse model. The results showed that (1) after administration of the WSGP (200 or 400 mg/kg/day), the feed intake, body weight, and colon length of colitic mice were increased, while the disease activity index and the histological score of colitic mice were decreased; (2) the WSGP reduced the colonic tissue damage and inhibited the expression of inflammatory factors (interleukin 6, interleukin 1 beta , and tumor necrosis factor alpha); and (3) the WSGP enhanced the production of short-chain fatty acids and improved the composition of intestinal microbiota. The key microorganisms, including Muribaculaceae, Lachnospiraceae, Lachnospiraceae_NK4A136_group, Mucispirillum, Helicobacter, Ruminococcus_1, and Ruminiclostridium_5, were identified to be associated with inflammatory bowel diseases. Taken together, this study proved that WSGP supplementation could alleviate DSS-induced colitis by improving mucosal barriers, blocking proinflammatory cytokines, and modulating gut microbiota.
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